Complications in patients with congenital insensitivity to pain and anhidrosis: a systematic review

Poppy Novita Rini 1 , Muhammad Syifa Irvandy 2 , Tifani Antonia Pradhea 3
Authors affiliations;
  1. Poppy Novita Rini, Ji Prof. Dr. H. Hadari Nawawi, Pontianak, 78124, West Kalimantan, Indonesia; Email; poppynovitarini@medical.untan.ac.id; {ORCID:0009-0007-2314-0881}
  2. Muhammad Syifa Irvandy, Ji Prof. Dr. H. Hadari Nawawi, Pontianak, 78124, West Kalimantan, Indonesia; Email; muhammadsyifairvandy130773@gmail.com; {ORCID:0009-0002-3510-1226}
  3. Tifani Antonia Pradhea, Ji Prof. Dr. H. Hadari Nawawi, Pontianak, 78124, West Kalimantan, Indonesia; Email; tifaniantonia@gmail.com; {ORCID:0009-0009-0223-826X}
Correspondence: Poppy Novita Rini, poppynovitarini@medical.untan.ac.id; Phone: 082158157558

 

ABSTRACT

 

Background. Congenital Insensitivity to Pain and Anhidrosis (CIPA) is a rare hereditary sensory and autonomic neuropathy type IV (HSAN IV) caused by NTRK1 gene mutations. It disrupts pain and temperature regulation, leading to anhidrosis, recurrent fever, self-injury, and, in severe cases, intellectual disability. The absence of pain perception increases the risk of unnoticed injuries and long-term complications. Understanding these complications is essential to improving patient care and quality of life.

Methodology:  A systematic search on PubMed, ScienceDirect, and ProQuest was conducted on October 30, 2024, using keywords related to CIPA and HSAN IV. This review included English-language clinical studies and case reports (2014–2024) reporting complications of CIPA. Reviews, books, inaccessible articles, and duplicates were excluded. A total of 29 case reports were analyzed, with quality assessed using JBI Critical Appraisal Tools.

Result. A total of 29 articles met the inclusion criteria, reporting complications among patients with CIPA. The most frequently observed complications were fever (87%), self-mutilation (73%), and recurrent fractures (68%), while developmental delay (63%) represented a major neurodevelopmental manifestation. The mean age of patients was 10.9 years, ranging from 1 to 38 years. Most reported cases originated from China (41%).

Conclusion. This review emphasizes the importance of early diagnosis in CIPA patients to prevent complications. However, current studies often lack comprehensive follow-up, which hinders our understanding of long-term outcomes. Further research is needed to fill these gaps and improve the quality of life for patients with this rare condition.

Abbreviations: CIPA: Congenital Insensitivity to Pain and Anhidrosis, HSAN IV: hereditary sensory and autonomic neuropathy type IV, NTRKI: neurotrophic tyrosine kinase 1,

Keywords: Congenital insensitivity to pain and anhidrosis, hereditary sensory and autonomic neuropathy type IV

Citation: Rini PN, Irvandy MS, Pradhea TA. Complications in patients with congenital insensitivity to pain and anhidrosis: a systematic review. Anaesth. pain intensive care 2025;29(6):1290-1301. DOI: 10.35975/apic.v29i6.3067

Received: February 16, 2025; Revised: November 02, 2025; Accepted: November 16, 2025

 

1. INTRODUCTION

 

Congenital Insensitivity to Pain and Anhidrosis (CIPA) is a rare form of hereditary sensory and autonomic neuropathy (HSAN) type IV, caused by a genetic mutation in the neurotrophic tyrosine kinase 1 (NTRK1) gene.1,2 This autosomal recessive condition disrupts the regulation of pain and temperature sensation, affecting multiple aspects of physical and neurodevelopmental functioning CIPA affects approximately 1 in 125 million people, with common symptoms such as recurrent fever, absence of sweating, insensitivity to pain, and a tendency to self-harm. In severe cases, patients may experience developmental delays or mental retardation.3 Chromosomal abnormalities in CIPA patients are reported to be mutations in neurotrophic tyrosine kinase 1 (NTRK1).2 The inability to sense pain impedes normal responses to injuries, making patients particularly vulnerable to infections and other complications.

The lack of connection between pain-sensing nerves and the brain’s pain-processing centers complicates early intervention and treatment in CIPA patients.4 Repeated complications can lead to the development of new, debilitating conditions, significantly reducing quality of life.5 Despite increased awareness of the disease's impact, research on its long-term complications remains limited. This study seeks to explore these complications to inform strategies aimed at improving the quality of life for CIPA patients.

 

2. METHODOLOGY

 

This systematic review was conducted based on the PRISMA 2020 Guideline.6 The search for the relevant studies was carried out on October 30, 2024, across international databases such as PubMed, ScienceDirect, and ProQuest. The protocol for this review has been registered with the International Prospective Register for Systematic Reviews (PROSPERO) under the registration number CRD42025606656.

The keywords for this study were selected based on the relevance to the research topics, using terms such as "Congenital Insensitivity to Pain and Anhidrosis" and "Hereditary Sensory and Autonomic Neuropathy Type IV,"  combined with the Boolean method (Table 1). This approach ensured that all relevant studies related to the topic were captured effectively.

 

Table 1: Boolean Operator
No Database Keyword dan boolean operator
1. PubMed (Congenital insensitivity to Pain and Anhidrosis) OR (Hereditary Sensory and Autonomic Neuropathy Type IV)
2. Science Direct congenital insensitivity to pain and anhidrosis OR hereditary sensory and autonomic neuropathy Type IV
3. ProQuest (congenital insensitivity to pain with anhidrosis) OR (hereditary sensory and autonomic neuropathy Type IV)
 

Clinical studies and case reports involving patients diagnosed with congenital insensitivity to pain and anhidrosis, articles published in English, free full-text availability, and publications from the last 10 years (2014–2024) were included. Exclusion criteria included studies that did not report complications, research using review methods (narrative reviews, systematic reviews, or meta-analyses), books or documents, articles in languages other than English, inaccessible articles, and duplicate studies, where only one version was considered.

Three reviewers (PNR, MSI, TAP) independently assessed titles and abstracts to identify potentially relevant studies. Subsequently, full-text articles were retrieved and evaluated for eligibility based on the inclusion and exclusion criteria. The JBI tool was utilized to assess the quality of the included case reports, categorizing criteria as “Yes,” “No,” or “Unclear” to increase credibility and facilitate collaboration between authors, while also extracting key information such as country of origin, patient demographics (e.g., sex, age, familial and parental marital history), genetic variants, and other clinical markers.7
Based on the critical appraisal using the JBI assessment, six of the eight appraisal questions were adequately addressed by more than 80% of the 29 reviewed articles, while the remaining two were met by over 58% of studies. However, several articles did not provide data presented according to a timeline, which limited the ability to evaluate disease progression. Nevertheless, most studies were able to supply sufficient data to support and strengthen the findings of this review. In contrast, studies providing detailed clinical, familial, and genetic data enhanced validity and introduced novel findings such as specific NTRK1 mutations and rare complications.

 



 

3. RESULTS

 

During the search for articles in the different databases (PubMed, Science Direct, and ProQuest),  97 articles were considered, which, upon a preliminary reading of titles and abstracts, were further reduced to 34 because did not fit in with the line of research pursued by this systematic review (e.g. the articles did not include any complication, the articles were review article or books, and duplicates). These 34 articles were selected for free full-text evaluation, and ultimately, this review includes 29 articles that were matched with inclusion criteria. Below is the flow diagram of the current systematic review. (Figure 1)

 



The critical appraisal of the included studies was conducted using JBI tools, as presented in Table 2, with a summary of the appraisal results provided in Figure 2. The detailed characteristics of all included studies are presented in Table 3, while Figure 3 provides a summarized overview of demographic distribution (sex, age, country) and complication percentages.

 











 

Study Outcomes
This study examined CIPA cases across multiple countries. A total of 29 articles analyzed 41 cases, with a gender distribution of 17 females (41%), 23 males (56%), and 1 unspecified. Most cases were reported from China (41%), Turkey (9%), Saudi Arabia (7%), Japan (7%), Korea (7%), India (4%), Pakistan (4%), and Indonesia (4%); while single cases (2% each) were identified from Palestine, Taiwan, Italy, America, and Jordan.8–36  Genetic mutations were identified in several cases, often from carriers without phenotypic expression.13,14,20–22,24 The mutations were homozygous (10 cases) or heterozygous (12 cases).8,13,14,17,21–24,30–33
The CIPA phenotype appeared in both familial and non-familial cases, including consanguineous marriages.8,12,14,17,19–23,25,26,29–31,33,35,36  Mortality data was limited, with only two patients reported deceased at 30 years of age.31,35
Among 41 cases, 34 had complications, including unexplained fever (87 %)9–17,19–27,30–36, self-injurious behavior (73 %) 8–36, recurrent fractures  (68%)8,10–14,16,17,19–22,24,28–31,34–36, developmental delay (63%)8–16,19–26,30,32,33,36. Some patients were  diagnosed with Riga-Fede, Lesch-Nyhan, Renal Amyloidosis, Nora Lesion, or ASD (12%).9,13,18,28–31,36 Other complications also included swelling, dislocation, ulceration, hyperkeratosis, infection, and Charcot arthropathy (9%).28,29,36
Clinically, all patients exhibited insensitivity to pain, with many presenting early self-mutilation behaviors, recurrent unexplained fevers due to anhidrosis, and frequent bone fractures and joint dislocations. Some cases also reported developmental delays, ASD, or neurological complications such as paraplegia. Genetic analysis revealed various NTRK1 mutations, including homozygous, heterozygous, and compound heterozygous forms, with some cases linked to consanguinity. Additional complications included recurrent infections, palmo-plantar hyperkeratosis, poor wound healing, and susceptibility to osteomyelitis. Several patients experienced hair loss, and antipyretics were often ineffective in managing fever. While most patients were alive at reporting, severe complications such as coma, respiratory failure, and paraplegia were observed.

 

4. DISCUSSION

 

The clinical manifestations commonly reported in CIPA patients across multiple studies include insensitivity to pain stimuli and anhidrosis.3 Based on the results of data collection, China has the highest number of reported CIPA cases, with 17 cases documented in the reviewed articles. However, there is limited research investigating the relationship between CIPA incidence and specific ethnic groups.

Among the 41 cases analyzed, 23 documented the marital history of the patients' parents.  Six cases involved patients with parents who were consanguineous, while 17 cases had parents without inbreeding. The inheritance pattern in CIPA is autosomal recessive, meaning that cases may or may not affect other family members. For instance, Hartono et al. (2020) reported a case in which a consanguineous couple had two children, both diagnosed with CIPA, due to both parents carrying mutations in the NTRK1 gene.35 In contrast, Wang et al. (2017) described a case where the patient’s siblings did not exhibit CIPA phenotypes, as the mutation occurred in the father, and the affected child acquired an additional de novo mutation independent of parental inheritance.20
The mean age of CIPA patients in the reviewed cases was 10.9 years, with the oldest patient being 38 years and the youngest 1 year old.9,29 However, these ages reflect the last recorded visits to healthcare facilities rather than actual life expectancy.  Ghorpade et al. (2023) suggested that CIPA patients rarely live beyond 25 years.37 Contrary to our literature review, surprisingly there were cases of CIPA patients living up to the age of 38 years and cases who died at the age of 30 years.29,31,35 The lack of long-term follow-up in many cases makes it difficult to fully understand the disease trajectory and lifespan of CIPA patients.

One of the hallmark clinical features of CIPA is anhidrosis, which results from mutations in the NTRK1 gene.2 This gene is essential for the development, differentiation, and maintenance of sensory and sympathetic neurons.21 Consequently, CIPA patients not only lose the ability to perceive pain but also experience impaired sweat gland function.33 Although histological analysis shows that their sweat glands appear structurally normal, their physiological function is disrupted, leading to an inability to regulate body temperature. As a result, recurrent febrile episodes commonly occur during the first two years of life.3,22 In some cases, antipyretics prove ineffective due to the absence of NTRK1-mediated neural regulation in the thermoregulatory system.19,21 Instead, conventional cooling methods, such as bathing, are often used to manage hyperthermia.20
The absence of pain perception in CIPA patients makes them highly susceptible to undetected injuries. Pain serves as a crucial warning signal triggered by nociceptive pathways, alerting individuals to potential harm.38 In CIPA patients, the inability to recognize trauma often leads to repeated injuries, which may go unnoticed unless accompanied by inflammation. Consequently, recurrent fractures, joint dislocations, and chronic wounds are common complications in these patients.

Self-mutilation is another significant characteristic of CIPA. This behavior is closely linked to the patient’s inability to perceive pain, with many cases reporting the onset of self-injurious behaviors during the teething process. However, not all CIPA patients exhibit self-mutilation.13,19,20,31 Among the 41 cases reviewed, three patients did not engage in self-harming behaviors, likely due to parental interventions and strict supervision.14,23 This finding highlights the role of behavioral and environmental factors in modulating self-mutilation tendencies.39,40 Additional complications, including swelling, ulceration, recurrent infections, joint dislocations, slow wound healing, hyperkeratosis, and Charcot arthropathy, were also frequently reported. These complications often result from repeated trauma and self-mutilation, underscoring the importance of parental education and close monitoring of affected children

Beyond physical injuries, neurological and developmental impairments are frequently observed in CIPA patients. Of the 41 cases analyzed, 26 reported delayed mental development. Zhang et al. (2022) noted that many CIPA patients exhibit intellectual disabilities, emotional instability, and hyperactivity.13  In addition, Bakri et al. (2016) reported that CIPA patients may develop inflammatory bowel disease due to immune system dysregulation.31 Furthermore, some patients have been diagnosed with coexisting conditions such as autism spectrum disorder (ASD) or Nora’s lesion. However, Zhang et al. found no direct correlation between NTRK1 mutations and the genetic mutations associated with ASD.13 Similarly, Colangeli et al. (2021) described a case of Nora’s lesion in a child with CIPA, though its etiopathogenesis remains unclear. These findings suggest that while CIPA primarily affects the nervous system, it may also contribute to broader systemic complications.18
Complications in CIPA patients show marked variability influenced by geography, sex, and age. Reports from China highlighted the broadest spectrum of complications—including autism spectrum disorder, recurrent dislocations, impaired healing, and severe infections—while Turkey, Korea, and Palestine described septic arthritis, palmar thickening, and poor weight gain, and cases from Pakistan, India, Japan, and Saudi Arabia more often reported Charcot arthropathy, musculoskeletal deformities, and life-threatening infections.8–10,12–15,22,24,27 Rare manifestations such as CNS perfusion abnormalities, Riga-Fede disease, and renal amyloidosis were also documented in select regions.16,30,31 Sex-based patterns were noted, with females more frequently showing alopecia, scoliosis, and osteomyelitis with amputation, while males often developed severe complications such as renal amyloidosis, respiratory failure, and sepsis.21,31,35 Age distribution further revealed that complications were most often identified in toddlers, followed by school-age children, underscoring age as a determinant of clinical presentation.8–16,18–21,25–27,30,32,36 Collectively, these findings emphasize that demographic and geographic factors substantially shape complication patterns and warrant further study to clarify underlying genetic, environmental, and healthcare-related influences.

 

5. CONCLUSION

 

Early diagnosis of CIPA is essential to reduce complications and improve patient outcomes. In this review, 87% of patients experienced recurrent fever, 73% self-mutilation, 68% fractures, and 63% developmental delay, indicating a substantial clinical burden. Most reported cases originated from China, likely reflecting a higher number of publications rather than true geographic prevalence. However, limited long-term follow-up—most patients were reported during childhood—hinders a full understanding of disease progression. Further longitudinal studies are needed to clarify genotype–phenotype correlations and improve the quality of life of affected individuals.
  1. Study Limitation and Further Recommendation
The reporting of complications varies based on research scope. This review identified a lack of longitudinal studies following patients from diagnosis to adulthood, which is essential for understanding disease progression and optimizing management strategies. Future research should focus on long-term cohort studies to clarify genotype–phenotype correlations, identify predictors of severe complications, and evaluate interventions that may improve survival and quality of life in CIPA patients.
  1. Data availability
The numerical data generated during this research is available with the authors.
  1. Conflict of interest
All authors declare that there was no conflict of interest.
  1. Funding
The study utilized the hospital resources only, and no external or industry funding was involved.
  1. Authors’ contribution
All authors took equal part in the literature search, analysis and compilation.

 

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